Scaffolding the Transition to Chronic Pain

搭建向慢性疼痛过渡的脚手架

基本信息

批准号：
9052231
负责人：
NATHANIEL Aaron JESKE
金额：
$ 31.41万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-01 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9052231
关键词：
A kinase anchoring protein Acute Address Adverse effects Affect Afferent Neurons Agonist American Analgesics Animal Model Animals Behavioral Behavioral Model Biochemical Biological Assay Caring Cell model Clinical Complex Coupled Data Dependence Development Drug Targeting Education Electrophysiology (science)Esthesia Genetic Transcription Glutamates Goals Health Hyperalgesia Institute of Medicine (U.S.)Ion Channel Knock-out Knowledge Lead Mechanics Mediating Methods Mission Modeling Molecular Molecular Genetics Mus Nerve Neuronal Plasticity Neurons Nociceptors Opioid Outcome Pain Pain Disorder Pain Research Pain management Pathway interactions Patients Peripheral Persistent pain Phosphorylation Post-Translational Protein Processing Preparation Preventive Intervention Proteins Public Health Quality of life Receptor Activation Regulation Research Research Project Grants Role Scaffolding Protein Sensory Serum Response Factor Skin Source Stimulus TRPV1 gene Testing Therapeutic Intervention Transcriptional Regulation Up-Regulation Work allodynia autocrine base central pain central sensitization chronic pain cost drug development experience feeding novel pain symptom receptor response scaffold therapeutic target

项目摘要

DESCRIPTION (provided by applicant): The long-term goal of this research project is to understand the role of scaffolding proteins in the regulation of nociceptor plasticity. Dynamic changes to proteins expressed in primary afferent terminals significantly alter pain sensation. For instance, ion channel phosphorylation can modulate channel activity, thereby affecting acute nocifensive responses to noxious stimuli. However, states of persistent pain likely rely on multiple mechanisms of dynamic protein modifications to maintain peripheral nociceptor sensitization. Therefore, nociceptor plasticity at the sensory terminal may exist to support persistent pain sensation. A large gap in knowledge exists concerning how neuroplastic changes in primary afferent neurons are integrated to contribute to the development of persistent pain. This represents an important unmet need, since the careful identification of molecular coordinators of persistent pain would provide new, peripheral therapeutic targets for analgesic drug development. The overall objective of this application is to identify that the development of persistent pain depends on autocrine nociceptor sensitization through a feed-forward, neuroplastic mechanism coordinated by A-Kinase Anchoring Protein 79/150 (AKAP). The central hypothesis for this application is that the scaffolding protein A-Kinase Anchoring Protein 79/150 (AKAP) coordinates nociceptor plasticity. This hypothesis will be addressed through three specific aims that (1) evaluate AKAP as an important coordinator of TRP channel sensitivity in cellular and behavioral models, (2) evaluate AKAP-dependence of feed-forward nociceptor sensitization, and (3) examine neuroplastic transcriptional control of AKAP expression. AKAP scaffolding mechanisms will be investigated through a combination of genetic, molecular, biochemical, behavioral and electrophysiology methods. The contribution of this research is significant because it is the first step towards developing novel peripherally active analgesics targeted at a key scaffolding mechanism of nociceptor plasticity. Research results will demonstrate that disrupting the scaffolding protein AKAP can significantly undermine neuroplastic changes in nociceptor excitability that contribute to the development of many clinical pain states.

描述（由申请人提供）：该研究项目的长期目标是了解支架蛋白在伤害感受器可塑性调节中的作用。初级传入末梢表达的蛋白质的动态变化显着改变痛觉。例如，离子通道磷酸化可以调节通道活性，从而影响对有害刺激的急性伤害反应。然而，持续性疼痛状态可能依赖于动态蛋白质修饰的多种机制来维持外周伤害感受器的敏化。因此，感觉末端的伤害感受器可塑性可能存在以支持持续的疼痛感。关于初级传入神经元的神经塑性变化如何整合以促进持续性疼痛的发展，目前的知识存在很大差距。这是一个重要的未满足的需求，因为仔细识别持续性疼痛的分子协调员将为镇痛药物的开发提供新的外周治疗靶点。本申请的总体目标是确定持续性疼痛的发展取决于自分泌伤害感受器敏化，通过由 A 激酶锚定蛋白 79/150 (AKAP) 协调的前馈神经塑性机制。该应用的中心假设是支架蛋白 A 激酶锚定蛋白 79/150 (AKAP) 协调伤害感受器可塑性。这一假设将通过三个具体目标来解决，即（1）评估 AKAP 作为细胞和行为模型中 TRP 通道敏感性的重要协调者，（2）评估前馈伤害感受器敏化的 AKAP 依赖性，以及（3）检查神经可塑性转录AKAP 表达的控制。 AKAP 支架机制将通过遗传、分子、生物化学、行为和电生理学方法的结合进行研究。这项研究的贡献是重大的，因为它是开发针对伤害感受器可塑性的关键支架机制的新型外周活性镇痛药的第一步。研究结果将证明，破坏支架蛋白 AKAP 可以显着破坏伤害感受器兴奋性的神经塑性变化，从而导致许多临床疼痛状态的发展。